Daylen Aguilar-Noriega and Silvio E. Perea. Volumen 4 / Número 4 • http://www.revistabionatura.com

LETTER TO EDITOR / CARTA AL EDITOR

Immunogenic Cell : An opportunity for Clinical Oncology?

Daylen Aguilar-Noriega and Silvio E. Perea. DOI. 10.21931/RB/2019.04.04.2 was initially seen as a kind of silent cell dea- presentation. Secreted HMGB-1 can bind to advanced th with non-induction of the immune response1. However, in glycation end products (RAGE), TLR2, and TLR4. However, the recent past, it has been seen that death induced by either TLR4 has been identified as the principal receptor for HMGB-1 infections or action of certain agents can elicit a specific im- that mediates anti-tumoral immune responses via chemothe- mune response, namely immunogenic (ICD)2. This rapy-induced ICD. The binding of HMGB-1 to TLR4 on DC was 958 ICD activates the immune system against associated shown to enhance the processing of phagocytic cargo, facili- with deceased cells with the concomitant exposure and relea- tate antigen presentation, and increase intracellular levels of sing of the so-called damage-associated molecular patterns pro-IL-1β. Importantly, knockdown of HMGB-1 or tumor cells (DAMPs) by dying cells3. Four principal DAMPs related to ICD deficient of HMGB-1 exhibit diminished capacity to induce ICD have been identified (but not limited to): the endoplasmic reti- and anti-tumor immune responses. culum (ER) chaperone (CRT), heat shock proteins In addition to hallmarks above mentioned, secreted type (HSPs), (ATP) and high mobility group I interferon, extracellular annexin A1 (ANXA1), and nucleic box-1 (HMGB-1)4. acids have also been described. During ICD process cytokines Today, DAMPS has been shown to play a spatiotemporal have been detected. The majority of those can be pro-inflam- role among the ICD process. For instance, CRT is a 46 kDa matory, which are involved in the increase of MHC class I on Ca2+-binding chaperone that is normally found in the lumen antigen-presenting cells expression, T cells differentiation, of ER, where it acts in Ca2+ homeostasis/signaling regulation and NK cells activation. However, its putative role in mediating and proper folding of proteins5. During induction of ICD, CRT is the ICD merits further investigation. (Figure 1) exposed on the outer surface of the plasmatic membrane ear- Beside great advances in understanding the molecular ly, in a pre-apoptotic stage, and serves as an “eat me” signal, and cellular events involved in ICD, new clinical perspectives stimulating to engulf portions of dead cells. CRT toward a more rational combination to treat arise from translocation occurs together with ERp57 but not of other ER this phenomenon. For instance, some standard anticancer proteins as a result of ER stress, which modulates the phos- drugs induce tumoral cell death with concomitant immuno- phorylation of eukaryotic translation initiation factor 2α (ei- genic signals. Most of these include chemotherapeutic agents F2α). Different reports have indicated that knockdown of CRT within them: (doxorubicin, epirubicin, idarubi- or ERp57 suppress the phagocytosis and the cin), (a platinum derivate), Cyclophosphamide (an of cell death, indicating the critical role that these proteins DNA-alkylating agent), bortezomib (a proteasomal inhibitor)9, play in ICD. The main receptor for CRT on myeloid cells is LDL mitoxantrone (an anthracenedione), bleomycin (a glycopeptide receptor-related protein 1 (LRP1; also known as CD91). antibiotic) and bortezomib (a proteasomal inhibitor) that have Heat shock proteins are also a class of chaperone pro- been employed in the clinic for several years. In addition to the teins involved in the synthesis, correct folding, subcellular chemotherapeutic agents, specific forms of irradiation10, high compartment transport, and degradation of intracellular pro- hydrostatic pressures11, some oncolytic viruses12, and microtu- teins6. These proteins are over-expressed under stress condi- bular inhibitor patupilone13,14 have also been shown to trigger tions, and they can be translocated to the plasma membrane ICD. However, predicting the ability of a compound to induce surface, and they can also be released into the extracellular or enhance ICD taking into account its structure, chemical pro- environment. The mainly HSPs involved in ICD is HSP70 and perties or functional similarities is not yet possible. HSP90. Accordingly, among the rational strategies currently On the other hand, ATP releasing constitutes a “find me” testing in clinical oncology to obtain better overall response signal for chemotaxis in ICD. ATP can attract macrophages against cancer are combinations of ICD inducers with immuno- and activates the NLRP3 , stimulating the final modulatory agents. Mainly, combinations with immunostimu- production of interleukin 1β (IL-1β), due to its action on cell latory cytokines, immune checkpoint inhibitors, adoptive im- surface purinergic receptors7. ATP release could occur for di- munotherapy, oncolytic or anticancer vaccines would fferent mechanisms, but premortem is the primary be a promising choice. mechanism that sustains high ATP levels in cells undergoing Definitively, the use of ICD bone fide inducing drugs find ICD. In fact, autophagy-deficient cancer cells fail to elicit the- a great opportunity in cancer treatment with putative great rapy-relevant immune responses in vivo. clinical benefit to patients with this disease. However, a priori Finally, High Mobility Group Box-1 (HMGB-1), is a non-his- identifying of novel anticancer ICD inducers is today a serious tone chromatin-binding protein considered as alarmin or mo- challenge to accomplish on the bench. lecular damage signal8. Extracellular HMGB-1 mediates nu- merous functions, including the activation of the endothelium and recruitment and maturation of cells of the immune sys- tem among which are the dendritic cells. ICD inductors elicit the passive release of HMGB-1 in a late-stage, which enhance

1 Cancer Department. Biomedical Research Area Center for Genetic Engineering and Biotechnology, Playa, Havana, Cuba.

Corresponding author: [email protected]. Immunogenic Cell Death: An opportunity for Clinical Oncology?

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Figure 1. Cancer and cytotoxic T-cells. T lymphocyte kills cancer cells. T-cell immune responses, release the perforin and granzymes, and attack cancerous cells. Through the action of perforin, granzymes enter the cytoplasm of the target cell, and lead to apoptosis cell death.

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